T lymphocyte function declines in advanced age leading to an increased susceptibility to infectious diseases, cancer and other ailments. Robust activation and activation-induced cell death (AICD) responses in T cells are required for healthy immunity and correlate with longevity in mice. The activation of young, healthy T cells is accompanied by a large increase in glucose flux and a concomitant increase in the expression and activity of metabolic enzyme genes and genes involved in the immune response. In addition, activation initiates AICD, a process that controls the population size of unwanted, autoreactive T cell clones. The co-stimulatory CD28 signaling pathway mediates the activation-induced increase in glucose metabolism. This highly conserved pathway is analogous to the IGF/insulin signaling pathway that determines lifespan in model systems ranging from C. elegans to mice. Our preliminary data demonstrate that high activation and AICD activities correlate with longevity in mice and that glucose metabolism is a determinant of AICD. T cells from the elderly display a diminished and delayed initial induction of CD28 signaling followed by a defective down-modulation of the CD28 signaling pathway several days later. The later effect may contribute to the decreased AICD seen in the elderly. In this study we will test the hypothesis that the CD28 signaling pathway and glucose metabolism play an important role in healthy immunity by examining the relationships between activation, glucose metabolism, AICD and healthy aging. In Specific Aim 1 we will determine the phenotype and activation capacity of T cells from all subjects in this study, and determine the quantitative and qualitative changes in CD8+CD28+ cells in different fitness groups of aging. In Specific Aim 2 we will determine differences in CD28 signaling and glucose metabolism in CD8+CD28 + cells in young versus aging subjects, and in different fitness groups of aging. In Specific Aim 3 will determine differences in AICD in CD8+CD28+ cells in young versus aging subjects, and in different fitness groups of aging. In Specific Aim 4 we will determine differences in activation-induced gene expression in CD8+CD28 + cells in young versus old subjects, and in different fitness groups of aging. The large population of nonagenarians in the present study, and our synergism with the other projects, provide a unique opportunity to determine how glucose metabolism contributes immune function and to the fitness of aging.